Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
PROCESS FOR THE PREPARATION OF TAMSULOSIN
FIELD OF THE INVENTION
The present invention relates to synthetic organic chemistry, specifically
tamsulosin as well as pharmaceutically acceptable salts thereof and to methods
for
their preparation.
BACKGROUND OF THE INVENTION
(R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-
methoxybenzenesulfonamide or tamsulosin has the following chemical formula:
oEt
I H
~ ~/ N S02NH2
O
'~ OMe
Tamsulosin is a known, commercially available drug, used in the treatment of
benign prostate hypertrophy. Tamsulosin is commonly prepared as its
hydrochloride salt.
Chemical synthesis of an organic compound of the complexity of tamsulosin
is commonly a mufti-stage, complicated process, where losses of yield of
intermediate products at various stages and requirements for purification of
intermediates at various stages can add up to an overall process of
unsatisfactory
yield and consequent economic disadvantage. Various processes for its
preparation are disclosed in the art.
United States Patent Nos. 4,703,063 and 4,558,156 as well as counterpart
European Patent No. 0,034,432, all of Imai et al., describe two processes for
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preparing tamsulosin, one of which involves the conversion of a hydroxy
substituted
analogue of tamsulosin, i.e., a compound having the tamsulosin structure but
having
a hydroxyl substituent at a position a to the benznesulphonamide ring, by
halogenation followed by either reduction or reaction with an alkali followed
by
hydrogen iodide; the other of which involves condensation of a
benzenesulfonamide
aldehyde with the appropriate substituted phenoxy amine, followed by reduction
of
the resulting imino product. These processes present some disadvantages. In
particular, a sulfonamide substituent is easily displaced from a benzene ring,
so that
subsequent chemical steps involving a benzenesulfonamide have to be conducted
with great care if yield is not to be lost. Moreover, the benzenesulfonamide
aldehyde compound prepared and used in these processes is an unstable oii.
Another significant disadvantage of these processes is that they are not
stereospecific, i.e., they are not suitable for the preparation of individual
optical
isomers of tamsulosin. The final products require a step of optical resolution
to
obtain specific optical isomers.
European Patent No. 0380144 of Okada et al., describes a process for
preparing tamsulosin and the like, in stereospecific form, by reaction of a
benzenesulfonamide amine with predetermined stereospecificity, with a
halogenated methyl phenyl ketone, specifically the bromide compound. This
bromide compound, however, is problematic in terms of purification and
storage.
Canadian Patent No. 1,340,332 of Koishi et al. describes an analogous
coupling reaction, but using an aldehyde for coupling with the amine instead
of the
ketone. This process suffers from similar disadvantages.
Published PCT Application WO 021068382 A1 of Ham et al. discloses a
process for the preparation of some sulfanoyl-substituted phenethylamine
derivatives including tamsulosin, which involves a coupling reaction between
(R)-5-
(2-amino)propyl-2-methoxy-benzenesulfonamide with an acid or a corresponding
acid chloride or mixed anhydride to obtain tamsulosin amide. This coupling
reaction
presents the disadvantage that the acid or acid chloride or anhydride should
be
provided in a high purity in order to obtain a good yield for the coupling
reaction; and
it is known in the art that purification of such products is not always easy.
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It is generally known in the art that formation of amide from direct reaction
between an ester and an amine is in general very difficult to achieve.
Successes in
such reaction have been reported in the following references: Basha, A.;
Lipton, M.;
Weinreb, S.M. Tetrahedron Lett. 1977, 4171-4.174. Levin, J.l.; Turos, E.;
Weinreb,
S.M. Synth. Comm. 1982, 12, 989-993. Huang, P-Q.; Zheng, X.; Deng, X-M.
Tetrahedron Letf. 2001, 42, 9039-9041. In these references, an aluminum
reagent
is used to activate the amine.
As can be seen, the various synthetic processes of tamsulosin described in
the above patents each present some disadvantages. Thus, there remains a need
for a practical, economic and efficient synthesis of tamsulosin, in optically
pure form.
SUMMARY OF THE INVENTION
It is thus an object of the present invention to provide an improved process
for the preparation of tamsulosin, which is reasonably simple, economic and
efficient.
It was the surprising discovery of the inventors that although known reactions
between an amine and ester to produce an amide are difficult to achieve, it is
possible to form tamsulosin amide with relative ease by coupling an ester of
general
formula 2A below with (R)-5-(2-amino)propyl-2-methoxy-benzenesulfonamide (3),
in
the presence of an aluminium reagent which activates amine (3), thus
facilitating the
coupling reaction. The reaction functions relatively well despite the presence
of the
sulfonamide group on the amine.
The invention provides, in one aspect, a process for the preparation of (R)-5-
[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide
(tamsulosin) of formula:
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oEt
I H
N S02NH2
O
OMe
and pharmaceutically acceptable salts thereof, which comprises coupling an
ester of
formula:
oEt
o'~cooR
za
5 with (R)-5-(2-amino)propyl-2-methoxy-benzenesulfonamide of formula:
HZN02S ~ NH2
Me0
3
in the presence of an aluminum reagent to yield tamsulosin amide of formula:
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H
N ~ S02NH2
O /,/
OMe
4
The aluminum reagent used in the coupling reaction between the ester (2A)
and the amine (3), as outlined above, is preferably a trivalent aluminum
reagent. It
can be selected from diisobutyl aluminum hydride, trimethyl aluminum, triethyl
aluminum, dimethyl aluminum chloride, aluminum isopropoxide and aluminum
trichloride. This coupling reaction is preferably carried out in the present
of an
aprotic solvent. Solvents reaction such as tetrahydrofuran, methylene
chloride,
toluene and benzene can be used.
The above amide (4) is reduced with a reducing agent to form tamsulosin (5)
above.
According to another aspect, the ester used in the coupling reaction is
obtained by reacting 2-ethoxy phenol with an alkyl halogeno acetate, in the
presence of a base. For example, methyl 2-ethoxyphenoxy acetate is obtained by
reacting 2-ethoxy phenol with methyl bromo acetate in the presence of
potassium
hydroxide. Preferred esters are alkyl esters, more preferably alkyl esters
wherein
the alkyl substituent is straight or branched and has 1 to 6 carbon atoms.
According to yet another aspect, the reduction reaction to yield tamsulosin is
carried out in the presence of a metal reagent, which can be an aluminum
reagent
or a borane reagent. More preferably, sodium bis(2-methoxyethoxy) aluminum
dihydride or borane dimethylsulfide can be used.
According to another aspect, the process comprises the further step of
treating tamsulosin with an acid to yield a pharmaceutically acceptable salt
thereof.
For example, tamsulosin is treated with hydrochloric acid to yield tamsulosin
hydrochloride salt.
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According to another aspect, the invention provides a process for the
preparation of tamsulosin, which comprises: reacting 2-ethoxy phenol with
methyl
bromo acetate in the presence of a base to obtain methyl 2-ethoxyphenoxy
acetate;
coupling 2-ethoxyphenoxy acetate with (R~5-(2-amino)propyl-2-methoxy-
benzenesulfonamide in the presence of diisobutyl aluminum hydride to obtain
tamsulosin amide; and subjecting tamsulosin amide to a reduction reaction in
the
presence of sodium bis(2-methoxyethoxy) aluminum dihydride or borane
dimethylsulfide to yield tamsulosin.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 is a reaction scheme illustrating the general process according to
the invention; and
FIGURE 2 is a reaction scheme illustrating a preferred embodiment of the
process according to the invention.
While the invention will be described in conjunction with the embodiments
illustrated in the reaction schemes, it will be understood that it is not
intended to limit
the invention to such embodiments. On the contrary, it is intended to cover
all
alternatives, modifications and equivalents as may be included within the
scope of
the invention as defined by the appended claims, including any reagents, steps
or
intermediate compounds that would be recognized as equivalent to those
described
herein by one skilled in the art.
DETAILED DESCRIPTION OF THE INVENTION
In the following description, molecules have been given similar reference
numerals as in the reaction schemes illustrated in the drawings.
Fig. 1 illustrates the general process according to the invention. 2-
Ethoxyphenol (1 ) is treated with an alkyl halogeno acetate in the presence of
a base
to yield an ester (2A). The ester is further subjected to a coupling reaction
with (R)-
5-(2-amino)propyl-2-methoxy-benzenesulfonamide (3) to yield tamsulosin amide
(4).
The coupling reaction is carried out in an aprotic solvent, in the presence of
an
aluminum reagent. This reaction is easy to perform and its success is tolerant
to the
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quality of the ester (2). Good results were obtained in a coupling reaction
carried
out using an ester sample contaminated with 10% of 2-ethoxyphenol.
Tamsulosin amide (4) may be further subjected to a reduction reaction to
yield tamsulosin (5), which can be further treated with an acid to yield a
salt of
tamsulosin (6A). Tamsulosin obtained through the process according to the
invention is in optically pure form. Indeed, the amine (R)-5-(2-amino)propyl-2-
methoxy-benzenesulfonamide (3) used has the appropriate stereochemistry, which
is transferred to the final product; no racemization occurred, either during
the
coupling reaction or during the reduction of tamsulosin amide.
The ester (2A) obtained after reaction of ethoxyphenol (1 ) with alkyl
halogeno
acetate can be used "as-is", without any purification for the coupling
reaction.
Turning to Fig. 2, there is illustrated an example embodiment of the process
according to the invention. The ester, 2-ethoxyphenoxy acetate (2) is obtained
by
treating 2-ethoxyphenol (1 ) with methyl bromo acetate in the presence of
potassium
hydroxide. The ester is further subjected to a coupling reaction with (R)-5-(2-
amino)propyl-2-methoxy-benzenesulfonamide (3) to yield tamsulosin amide (4).
The coupling reaction is carried out in tetrahydrofuran, in the presence of
diisobutyl
aluminum hydride.
Tamsulosin amide (4) is further subjected to a reduction reaction, using
either
sodium bis(2-methoxyethoxy) aluminum dihydride or borane dimethylsulfide, to
yield
tamsulosin (5), which can be further treated with hydrochloric acid to yield
tamsulosin hydrochloride salt (6).
EXAMPLE 1: Formation of methyl 2-ethoxyphenoxy acetate (2)
A 500 ml three-neck, round bottom flask was charged with 6.25 ml of water
and 6.55g of potassium hydroxide. The resulting mixture was gently stirred at
ambient temperature to give a clear solution. The resulting mixture was
further
charged with 250 ml of toluene and 11.5 ml of 2-ethoxyphenol (75 g), then
heated to
reflux. Water distilled out of the reaction mixture was collected in the Dean-
Stark
trap. After 3 hours of heating, distillation of water from the reaction
mixture had
stopped. The reaction mixture was allowed to cool to room temperature. A
solution
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of 11.2 ml of methyl bromoacetate and 12.5 ml of toluene was added to the
reaction
vessel over a period of 10 minutes, resulting in a white suspension which was
allowed to stir vigorously at room temperature for 2 hours. Then, 65 ml of
water and
4.86 ml of ethylenediamine were added. The resulting biphasic mixture was
stirred
vigorously for 60 minutes. The mixture was transferred to a 500 ml separatory
funnel and the biphasic layer was separated. The organic layer was collected
and
washed with diluted HCI solution, followed by water. The organic extract was
filtered
and the resulting solution was concentrated via atmospheric distillation. This
solution of ester 2 in toluene was used "as-is" for the next reaction.
EXAMPLE 2: Formation of tamsulosin amide (4)
A 500 ml three-necked, round bottom flask was charged with 15.12g of amine
3 and 76 ml of THF. With moderate stirring under nitrogen, a heavy white
suspension was formed. The suspension was then cooled in an ice-water bath to
0-
5°C. With moderate stirring, 65 ml of a 1 M solution of
diisobutylaluminum hydride
in THF was added to the suspension at a rate such that the batch temperature
was
maintained at 5-10°C. After the addition was completed, the mixture was
stirred at
5-10C for 5 minutes to give a light white suspension. The cooling bath was
removed and the mixture was allowed to warm to 20-25°C and agitated for
1 hour at
this temperature. With moderate agitation, 13.02 g of 2 in toluene was charged
into
the mixture via a syringe. The resulting reaction mixture was stirred at 20-
25°C for
16 hours and then cooled in an ice-water bath to 0-5°C. With vigorous
agitation,
HCI was charged in slowly such that the reaction temperature was maintained at
20-
25°C. A heavy white suspension was formed. The above suspension was
transferred to a 1 L Erlenmeyer flask equipped with a magnetic stirring bar
with the
aid of CH2CI2. This mixture was stirred vigorously for 30 minutes at 20-
25°C to give
a biphasic solution. The layers were separated and the lower organic layer was
collected and washed with water. The cloudy solution was filtered and
concentrated
via distillation under atmospheric pressure. The solution was cooled to 40-
50°C and
ethanol was added. The resultant solution was again concentrated via
distillation
under atmospheric pressure to generate a heavy white suspension. The heavy
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white suspension obtained above was cooled to 20-25°C. With moderate
stirring,
MTBE was charged. The resultant mixture was stirred for 5 minutes and then
cooled in an ice-water bath to 0-5°C. Agitation continued for another
30 minutes.
The white solid in the suspension was collected by suction filtration while
cold. The
cake was collected and dried under vacuum at 45°C for 16 hours to give
20.2 g of
the amide 4 with a yield of 77%.
EXAMPLE 3: Formation of tamsulosin hydrochloride (6) using borane-
dimethylsulfide
A 1 L, 3 necked round bottom flask equipped with a condenser, a mechanical
stirrer, a thermometer and a nitrogen inlet, was charged 47.4 g of 4 with 500
mL of
THF. The resulting suspension was brought to reflux. While maintained at
reflux,
the reaction solution was charged slowly and carefully with borane-
dimethylsulfide
(63.8 mL). The reaction mixture was continued with the reflux for 5 hours at
which
point the reaction was usually seen complete by HPLC.
Next, the mixture was cooled to room temperature and concentrated to
dryness to give a thick pale yellow oil. To this oil, methanol (300 mL) and 7
M
ethanol/HCI solution (100 mL) were added and the resulting white suspension
was
refiuxed for 0.5 hour. Then, the mixture was evaporated to dryness to give
white
solid. The solid was dissolved in refluxing methanol (300 mL) and then, cooled
to
room temperature. Diethyl ether (500 mL) was added and the suspension was
stirred at room temperature for a period of 2 hours. The solid was filtered
and
washed with cold MeOH/diethyl ether solution (1:3, 80 mL). The white solid was
vacuum dried at 40°C overnight to give 44 g of the product (6) (92%
yield).
EXAMPLE 4: Formation of tamsulosin hydrochloride (6) using sodium bis(2-
methoxyethoxy)aluminum hydride
Toluene (60 mL) was added into a round bottom flask containing 6.33 g of 4.
The resulting suspension was stirred moderately under nitrogen at 5-
10°C. Excess
sodium bis(2-methoxyethoxy)aluminum hydride (Red-AI, 6.5 equivalents) was
slowly
charged into this suspension. The reaction mixture was agitated at ambient
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temperature overnight (21 hours). The reaction was quenched with aqueous
hydrochloric acid and the crude tamsulosin hydrochloride was isolated.
Purification
of the crude product was accomplished by the liberation of the free base from
the
crude HCI salt with sodium hydroxide and then the extraction of the amine into
dichloromethane followed by the regeneration of the salt with HCI in ether.
This
material was further purification by recrystallisation from methanol. The
final
product was isolated as a crystalline white powder in 71 % yield (4.75 g).
It is apparent that there has been provided in accordance with the invention a
never and improved process for the preparation of tamsulosin as well as
pharmaceutically acceptable salts thereof. The process of the invention is
simple,
economic and efficient, yielding tamsulosin in optically pure form.
